Differences in clinical characteristics among 726 patients with Chinese herbal medicine- or Western medicine-induced liver injury.

The differences between Chinese herbal medicine (CHM)- and Western medicine (WM)-induced liver injury have rarely been reported. Our aim was to investigate the clinical features of patients with drug-induced liver injury (DILI) caused by CHM or WM. The medical records of 726 DILI patients were retrospectively collected at Peking University First Hospital from January 1995 through August 2019. The number of inpatients with DILI in our hospital showed an increasing trend over time. The incidence of DILI caused by CHM exhibited a linear trend toward an increase with time (P = .0012). Of the 726 DILI patients, females accounted for 65.8%. There were 353 cases (48.6%) caused by CHM and 225 cases (40.0%) caused by WM. The 3 most common causative CHMs were Polygonum multiflorum (38 cases), Fructus Psoraleae (35 cases), and Epimedium (26 cases). The proportions of female patients, alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, total bilirubin (TBIL) levels and antinuclear antibody (ANA) positivity rates among cases caused by CHM were higher than those of cases caused by WM (P < .05). There were more patients with severe cases caused by CHM than with severe cases caused by WM (P < .05). The clinical characteristics of DILI caused by CHM differ from those caused by WM. The incidence of DILI caused by CHM is increasing yearly. The medication time of DILI caused by CHM is longer than that of DILI caused by WM, and the severity is greater. Therefore, it is necessary to scientifically and rationally use traditional CHM and monitor liver function. For DILI caused by CHM, the CHM prescription should be recorded in detail to provide detailed clinical data for scientific research on the liver toxicity of CHM.

Discharge may not be the end of treatment: Pay attention to pulmonary fibrosis caused by severe COVID-19.

Since December 2019, coronavirus disease (COVID-19) has rapidly swept the world. So far, more than 30 million people have been infected and nearly one million have died. Although the world is still in the stage of COVID-19 pandemic, the treatment of new cases and critically ill patients is the focus of the current work. However, COVID-19 patients lead to pulmonary fibrosis, such a serious threat to the prognosis of complications were also worthy of our attention. First of all, we proposed the possible mechanism of pulmonary fibrosis caused by SARS-CoV-2, based on the published data of COVID-19 ((i) Direct evidence: pulmonary fibrosis was found in autopsy and pulmonary puncture pathology. (ii) Indirect evidence: increased levels of fibrosis-related cytokines[transforming growth factor [TGF]- ß, tumor necrosis factor [TNF]- α, interleukin [IL]-6, etc] in peripheral blood of severe patients.) What is more, we summarized the role of three fibrosis-related signaling pathways (TGF- ß signal pathway, WNT signal pathway and YAP/TAZ signal pathway) in pulmonary fibrosis. Finally, we suggested the therapeutic value of two drugs (pirfenidone and nintedanib) for idiopathic pulmonary fibrosis in COVID-19-induced pulmonary fibrosis.

Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population.

BACKGROUND: Polygonum multiflorum is one of the leading causes of herb-induced liver injury in China. HLA-B*35:01 is reported to be a potential biomarker of Polygonum multiflorum-induced liver injury (PM-DILI). However, little is known about the relationship between single-nucleotide polymorphisms (SNPs) and PM-DILI. AIM: To identify SNPs that indicate susceptibility to PM-DILI. METHODS: We conducted a systematic study enrolling 382 participants from four independent hospitals, including 73 PM-DILI patients, 118 patients with other drug-induced liver injury (other-DILI) and 191 healthy controls. Whole-exome sequencing was performed for 8 PM-DILI patients and 8 healthy controls who were randomly selected from the above subjects. Nineteen SNPs that showed high frequencies in the 8 PM-DILI patients were selected as candidate SNPs and then screened in 65 PM-DILI patients, 118 other-DILI patients and 183 healthy controls using the MassARRAY system. HLA-B high-resolution genotyping was performed for the 73 PM-DILI and 118 other-DILI patients. The Han-MHC database was selected as a population control for HLA-B analysis. P < 6.25 × 10-3 after Bonferroni correction was considered significant. RESULTS: The frequencies of rs111686806 in the HLA-A gene, rs1055348 in the HLA-B gene, and rs202047044 in the HLA-DRB1 gene were significantly higher in the PM-DILI group than in the control group [27.2% vs 11.6%, P = 1.72 × 10-5, odds ratio (OR) = 3.96, 95% confidence interval (CI): 2.21-7.14; 42.5% vs 8.6%, P = 1.72 × 10-19, OR = 13.62, 95%CI: 7.16-25.9; 22.9% vs 8.1%, P = 4.64 × 10-6, OR = 4.1, 95%CI: 2.25-7.47]. Only rs1055348 showed a significantly higher frequency in the PM-DILI group than in the other-DILI group (42.5% vs 13.6%, P = 1.84 × 10-10, OR = 10.06, 95%CI: 5.06-20.0), which suggested that it is a specific risk factor for PM-DILI. rs1055348 may become a tag for HLA-B*35:01 with 100% sensitivity and 97.7% specificity in the PM-DILI group and 100% sensitivity and 98.1% specificity in the other-DILI group. Furthermore, HLA-B*35:01 was confirmed to be associated with PM-DILI with a frequency of 41.1% in the PM-DILI group compared with 11.9% (P = 4.30 × 10-11, OR = 11.11, 95%CI: 5.57-22.19) in the other-DILI group and 2.7% (P = 6.22 × 10-166, OR = 62.62, 95%CI: 35.91-109.20) in the Han-MHC database. CONCLUSION: rs111686806, rs1055348, and rs202047044 are associated with PM-DILI, of which, rs1055348 is specific to PM-DILI. As a tag for HLA-B*35:01, rs1055348 may become an alternative predictive biomarker of PM-DILI.

Deficiency of canonical Wnt/ß-catenin signalling in hepatic dendritic cells triggers autoimmune hepatitis.

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease manifested with the aberrant activation of hepatic dendritic cells (HDCs) and the subsequent breakdown of immune homeostasis. As an important player, HDC maintains immunological balance between tolerance to self-antigens versus destruction against pathogens in liver. However, the intracellular signalling networks that program HDC remain unclear. We have now found the role of canonical Wnt/ß-catenin signalling in HDCs. METHODS: Liver sections from AIH patients and healthy subjects were stained for the markers of Wnt/ß-catenin signalling. Concanavalin A (ConA) and HDC/Hepa1-6 vaccine-induced AIH mouse models were examined for liver injury, inflammation and immune cell functions by serum biochemistry, histology, quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry analysis. Wnt/ß-catenin signalling expression was measured using immunoblot and qRT-PCR. RESULTS: Canonical Wnt/ß-catenin signalling in HDC is deficient in AIH patients and a mouse model, which coincides with the immunogenic function of HDCs. Furthermore, Wnt ligand engagement reactivates Wnt/ß-catenin signalling and recovers the immunoregulatory phenotype of HDCs, in turn alleviating the severity of AIH. Likewise, pharmacologic activation of Wnt/ß-catenin signalling attenuates AIH progression. CONCLUSIONS: We report here that the constitutively active canonical Wnt/ß-catenin signalling confers HDCs tolerogenicity under steady-state conditions. Deficiency of this pathway gives rise to T cell-mediated immune response and incidence of AIH. It may act as a new pathogenesis and treatment target for AIH.

Characteristics of the gut microbiota in professional martial arts athletes: A comparison between different competition levels.

Recent evidence suggests that athletes have microbial features distinct from those of sedentary individuals. However, the characteristics of the gut microbiota in athletes competing at different levels have not been assessed. The aim of this study was to investigate whether the gut microbiome is significantly different between higher-level and lower-level athletes. Faecal microbiota communities were analysed with hypervariable tag sequencing of the V3-V4 region of the 16S rRNA gene among 28 professional martial arts athletes, including 12 higher-level and 16 lower-level athletes. The gut microbial richness and diversity (the Shannon diversity index (p = 0.019) and Simpson diversity index (p = 0.001)) were significantly higher in the higher-level athletes than in the lower-level athletes. Moreover, the genera Parabacteroides, Phascolarctobacterium, Oscillibacter and Bilophila were enriched in the higher-level athletes, whereas Megasphaera was abundant in the lower-level athletes. Interestingly, the abundance of the genus Parabacteroides was positively correlated with the amount of time participants exercised during an average week. Further analysis of the functional prediction revealed that histidine metabolism and carbohydrate metabolism pathways were markedly over-represented in the gut microbiota of the higher-level athletes. Collectively, this study provides the first insight into the gut microbiota characteristics of professional martial arts athletes. The higher-level athletes had increased diversity and higher metabolic capacity of the gut microbiome for it may positively influence athletic performance.

Diagnostic value of angiopoietin-like protein 2 for CHB-related hepatocellular carcinoma.

PURPOSE: Angiopoietin-like protein 2 (ANGPTL2) is a secretory glycoprotein with various functions in vascular biology, inflammation and tumor development. As shown in our previous studies, ANGPTL2 expression positively correlates with liver fibrosis stages in chronic hepatitis B (CHB) patients. The aim of this study was further to assess whether ANGPTL2 represents a potential biomarker for detecting hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This study enrolled 361 participants including healthy controls (HCs) and patients with CHB, liver cirrhosis (LC) and HCC. A discovery cohort consisted of 35 HCs and 55 patients with HCC. A total of 271 participants, including 45 HCs, 125 patients with CHB, 38 patients with LC, and 63 patients with HCC were enrolled in a validation cohort. Serum ANGPTL2 levels were detected using a human ANGPTL2 assay kit, and hepatic expression of ANGPTL2 was analyzed using immunohistochemistry. RESULTS: In the discovery cohort, a significantly higher serum ANGPTL2 level was detected in HCC than in HCs (73.49±33.87 vs 30.54±9.86; p<0.001). The results of the receiver operating characteristic curve indicated a significantly higher area under the curve for the ability of the ANGPTL2 to predict HCC than alpha fetoprotein (AFP). In the validation cohort, serum ANGPTL2 level gradually increased with the progression of chronic hepatitis B virus infection and reached the highest level in HCC. Immunohistochemical staining also confirmed these findings. The serum ANGPTL2 displayed better diagnostic efficiency not only for differentiating HCC from HC but also for differentiating HCC from high-risk controls (CHB+LC). Furthermore, the combination of ANGPTL2 and AFP may increase the diagnostic accuracy for HCC compared to ANGPTL2 or AFP alone. Importantly, ANGPTL2 levels also correlated with the detection of AFP-negative HCC. CONCLUSIONS: ANGPTL2 may be used as a promising biomarker for the diagnosis of CHB-related HCC.

A human ciliopathy with polycystic ovarian syndrome and multiple subcutaneous cysts: A rare case report.

RATIONALE: Ciliopathies is a group of clinically and genetically overlapping disorders due to cilia abnormalities and multiple organ systems are involved in. PATIENT CONCERNS: We present a young female patient who showed renal function impairment, Caroli syndrome (CS), liver cirrhosis, polycystic ovarian syndrome, and multiple subcutaneous cysts. DIAGNOSES: The patient was diagnosed with ciliopathy according to the clinical manifestations and whole-genome sequencing. INTERVENTIONS: She received treatment of intravenous albumin, polyene phosphatidyl choline, furosemide, and antisterone. OUTCOMES: The patient showed clinical improvement in her edema and liver tests, and ultrasonography revealed that the ascites had disappeared. Unfortunately, the edema relapsed a year later. The patient received the same treatment as before, and there was clinical improvement of the edema. Since the family cannot afford liver and kidney transplantation, the patient only accepted symptomatic treatment. LESSONS: Polycystic ovarian syndrome and multiple subcutaneous cysts have never before been reported to be associated with ciliopathy. This finding could remind doctors to consider the possibility of ciliopathy disease for patients suffering from similar conditions. In addition, the phenotype of the patient differs from those of patients reported with the same mutations, which also reminds doctors that the clinical manifestation of a given mutation may show patient-specific differences. This case report extends the phenotypic spectrum of ciliopathy, and these findings might represent a new ciliopathy syndrome, which could facilitate the diagnosis of ciliopathies.

Features and outcomes from a retrospective study of 570 hospitalized Chinese patients with drug-induced liver injury.

AIMS: To investigate the clinical features and outcomes of hospitalized patients with drug-induced liver injury (DILI). METHODS: The medical records of hospitalized patients with DILI from January 1997 through July 2016 were reviewed. RESULTS: Five hundred seventy cases were reviewed, of which 381 (66.8%) were female. Four hundred fifty-eight cases (80.4%) presented with hepatocellular injury, 53 (9.3%) with cholestatic injury and 59 (10.4%) with mixed injury. Chronicity was more common in cholestatic and mixed injury cases than in hepatocellular cases (P<0.001). In the hepatocellular injury group, patients in the severity score≥3 group were younger than the patients in the severity score≤2 group (P=0.040). In the entire cohort, 487/570 (85.4%) patients resolved, 57/570 (10.0%) developed chronic liver injury, and 11/570 (1.9%) died. Thirty-two acute DILI patients with severity scores of 3 received steroid therapy, but no improvement was observed in the recovery time or resolution rate of these patients compared with that of the non-steroid group. Chinese herbal medicines were the most commonly used drugs, followed by antimicrobials, cardiovascular agents, endocrine agents, and nonsteroidal anti-inflammatory drugs (NSAIDs). CONCLUSIONS: Hepatocellular injury was the most common DILI pattern, and 10.0% of patients developed chronic DILI. Steroid therapy was not associated with an improved recovery time or survival in acute severe DILI patients.

The Molecular Mechanisms of Ciprofloxacin Resistance in Clinical Campylobacter jejuni and Their Genotyping Characteristics in Beijing, China.

We assessed the susceptibility of 182 Campylobacter jejuni isolates from patients with diarrhea to eight antibiotics and analyzed the molecular mechanisms of ciprofloxacin resistance as well as the genetic characteristics based on multilocus sequence typing (MLST). The C257T mutation was found on the quinolone resistance-determining region (QRDR) of the gyrA gene in all ciprofloxacin-resistant strains. Mutations on the QRDR of the gyrB gene were silent. A total of 74 strains had 7 inverted repeat (IR) (a 16-bp IR on the intergenic region between cmeR and cmeABC) mutation polymorphisms. Compared with strains without the IR mutations, strains with the IR mutations had higher resistance rates to ciprofloxacin (94.6% vs. 83.3%), nalidixic acid (94.6% vs. 83.3%), tetracycline (98.6% vs. 85.2%), doxycycline (91.9% vs. 71.3%), florfenicol (59.5% vs. 17.6%), chloramphenicol (25.7% vs. 4.6%), gentamicin (16.2% vs. 3.7%), and multidrug resistance than those without IR mutations (all p < 0.05). With C257T mutation alone, 89.9% strains with minimum inhibitory concentration (MIC) values focused on 16, 32, and 64 µg/mL, whereas strains with C257T mutation in combination with the IR mutations had a higher ciprofloxacin resistance level with 88.6% MIC values focused on 64, 128, and 512 µg/mL (p < 0.0001). The strains in this study showed a high genetic variability based on MLST with 117 sequence types (STs), 37 of which were novel. CC-21 was the most common clonal complex (CC) followed by CC-353 and CC-45. No association was found between STs and ciprofloxacin resistance. In conclusion, the C257T mutation on gyrA was the major mechanism for ciprofloxacin resistance, and the C257T mutation in combination with the IR mutations might result in more severe ciprofloxacin resistance to C. jejuni.

A seventeen-year observation of the antimicrobial susceptibility of clinical Campylobacter jejuni and the molecular mechanisms of erythromycin-resistant isolates in Beijing, China.

OBJECTIVES: To investigate the dynamic development of the antimicrobial resistance of Campylobacter jejuni isolated from human diarrhea in Beijing, China, between 1994 and 2010, and to further analyze the molecular mechanisms of erythromycin-resistant strains. METHODS: Susceptibility tests were performed on 203 non-duplicate clinical C. jejuni strains against eight common antibiotics using the standard agar dilution method. The molecular determinants were further studied in the erythromycin (ERY) non-susceptible strains. The analysis focused on the 23S rRNA gene, the rplD and rplV ribosomal genes, the ermB gene, and the regulatory region of the CmeABC efflux pump. RESULTS: The rates of resistance of C. jejuni to ciprofloxacin (CIP), nalidixic acid (NAL), doxycycline (DOX), tetracycline (TET), florfenicol (FFC), and chloramphenicol (CHL) increased significantly over the period studied (all p<0.05). Similarly, the proportions of resistant patterns (CIP-NAL-DOX-TET, CIP-NAL-DOX-TET-FFC, and CIP-NAL-DOX-TET-CHL) increased remarkably. In this study, 4.4% (9/203) of C. jejuni strains were ERY non-susceptible. The A2075G mutation in the 23S rRNA was found in all of the resistant strains except cj8091, which harbored the ermB gene. Interestingly, the ermB gene was also detected in intermediately resistant isolates, and the earliest ermB-positive strain cj94473 was derived in 1994. Moreover, none of the ribosomal rplD or rplV genes harbored mutations that have been described to confer resistance to macrolides. Different mutations affecting the regulatory region of the CmeABC efflux pump were also found. CONCLUSIONS: This is the first comprehensive study on the recent trend in antimicrobial resistance and the molecular mechanisms of macrolide resistance in clinical C. jejuni strains isolated in China. More stringent monitoring and regulation of human and animal antimicrobial use are warranted.